Dehydroepiandrosterone and its sulfate (DHEA(S)) show a cycle of large changes in secretion from the adrenal cortex over the life span in humans. The secretion of these steroids is very high in the fetus, low in childhood, high again in young adulthood, followed by a progressive age- related decline. Dependent on age, 40-100% of local tissue androgens and estrogens in both men and women are derived from DHEAS. The critical regulatory point in the biosynthesis of DHEAS is 3beta- hydroxysteroid/delta4 '5-isomerase (3beta-HSD). The low level of activity of this enzyme in the human adrenal cortex, but not in animal glands such as that of the cow, limits the flux of pregnenolone to A steroids, such as cortisol, and maintains the synthesis of delta5 steroids, principally DHEA(S). The proposed experiments will analyze the differences between the type Il human 3beta-HSD gene, which is expressed in the adrenal cortex and other steroidogenic tissues, and the 3beta-HSD gene expressed in the bovine adrenal. Transcription rates and mRNA stability will be assessed as possible causes of the differences in 3beta-HSD expression between the bovine and human adrenal cortex, and between the different zones of the human adrenal cortex. The bovine 3beta-HSD gene (or genes) expressed in the adrenal cortex will be isolated, its structure analyzed, and the tissue distribution of its transcript determined. The difference in expression levels between the human type Il and the bovine gene will be tested using reporter constructs from the two genes transfected into primary human and bovine adrenal cells. The elements in the type II human and the bovine 3beta-HSD genes responsible for tissue-specific expression and second messenger regulation, and nuclear proteins from the adrenal cortex that bind to these elements, will be characterized. The possible identity of such proteins to known transcription factors will be tested. Cell culture experiments will examine whether the cycle of DHEAS synthesis over the life span in humans results from intrinsic changes in expression of 3beta-HSD. The abundance in adrenocortical tissue of nuclear proteins that bind to the regulatory elements of the type II 3beta-HSD gene will be correlated with the cycle. These experiments will elucidate the molecular basis for the regulation of the human 3beta-HSD type II gene and thereby the regulation of DHEAS synthesis. This information will provide a basis for understanding the significance of the unique secretion of this hormone in humans and the significance of its age-related decline for aging and age-related diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG012287-01A1
Application #
2053796
Study Section
Endocrinology Study Section (END)
Project Start
1994-09-30
Project End
1998-08-31
Budget Start
1994-09-30
Budget End
1995-08-31
Support Year
1
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Other Health Professions
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
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Nakamura, Yasuhiro; Hornsby, Peter J; Casson, Peter et al. (2009) Type 5 17beta-hydroxysteroid dehydrogenase (AKR1C3) contributes to testosterone production in the adrenal reticularis. J Clin Endocrinol Metab 94:2192-8
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Liu, Dan; Hornsby, Peter J (2007) Fibroblast stimulation of blood vessel development and cancer cell invasion in a subrenal capsule xenograft model: stress-induced premature senescence does not increase effect. Neoplasia 9:418-26
Casson, Peter R; Buster, John E; Callas, Peter M et al. (2007) Human chorionic gonadotropin does not alter patterns of adrenal androgen secretion in primary human adrenal reticularis and fasciculata cell culture. Menopause 14:316-9
Liu, Dan; Hornsby, Peter J (2007) Senescent human fibroblasts increase the early growth of xenograft tumors via matrix metalloproteinase secretion. Cancer Res 67:3117-26
Chen, M; Hornsby, P J (2006) Adenovirus-delivered DKK3/WNT4 and steroidogenesis in primary cultures of adrenocortical cells. Horm Metab Res 38:549-55
Hornsby, Peter J (2005) Replicative senescence and cancer. Cancer Treat Res 124:53-73
Sun, Beicheng; Chen, Meizhen; Hawks, Christina L et al. (2005) Immortal ALT+ human cells do not require telomerase reverse transcriptase for malignant transformation. Cancer Res 65:6512-5

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